Synthesis and antioxidant activity of styrylsulfonylmethyl 1,3,4-oxadiazoles, pyrazolyl/isoxazolyl-1,3,4-oxadiazoles

Article abstract of DOI:10.1248/cpb.c13-00652

A new class of mono and bis heterocycles-styrylsulfonylmethyl 1,3,4-oxadiazoles, pyrazolyl/isoxazolyl- 1,3,4-oxadiazoles were prepared and studied their antioxidant activity. The compound methyl substituted 2-(p-methylphenylamino-sulfonylmethyl)-5-[Z-(p-m

Full text of DOI:10.1248/cpb.c13-00652

December 2013
Regular Article
Chem. Pharm. Bull. 61(12) 1291–1297 (2013)
1291
Synthesis and Antioxidant Activity of Styrylsulfonylmethyl
1,3,4-Oxadiazoles, Pyrazolyl/Isoxazolyl-1,3,4-oxadiazoles
Guda Mallikarjuna Reddy,a Akkarapalli Muralikrishna,a Venkatapuram Padmavathi,a
,a
Adivireddy Padmaja,* Thandaiah Krishna Tilak,b and Chippada Appa Raob
b
a Department of Chemistry, Sri Venkateswara University; and Department of Biochemistry, Sri Venkateswara
University; Tirupati 517 502, Andhra Pradesh, India.
Received August 18, 2013; accepted September 20, 2013
A new class of mono and bis heterocycles-styrylsulfonylmethyl 1,3,4-oxadiazoles, pyrazolyl/isoxazolyl-
1,3,4-oxadiazoles were prepared and studied their antioxidant activity. The compound methyl substituted
2-(p-methylphenylamino-sulfonylmethyl)-5-[Z-(p-methylstyrylsulfonylmethyl)]-1,3,4-oxadiazole displayed
slightly higher antioxidant activity than the standard ascorbic acid.
Key words pyrazolyl; isoxazolyl oxadiazole; nitrile imine; nitrile oxide; antioxidant activity
Nitrogenꢀcontainingꢀfive-memberedꢀheterocyclicꢀcompoundsꢀ olefinꢀ moietyꢀ presentꢀ inꢀ compoundꢀ 3 was utilized to develop
have gained intensive research interest as they possess a wide pyrazolesꢀandꢀisoxazolesꢀwithꢀappropriateꢀdipolarꢀreagents-ni-
range of applications in pharmaceutical and agrochemistry.1–3) trile imine and nitril oxide. In the literature it was reported that
In fact, pyrazole, isoxazole and oxadiazole motifs make up theꢀ cycloadditionꢀ ofꢀ 1,3-dipolarꢀ reagentsꢀ toꢀ α,β-unsaturatedꢀ
the core structures of numerous natural products and biologi- systems proceeds in such a way that the electron rich atom of
cally active synthetic compounds.4–9)ꢀ Substitutedꢀ 1,3,4-oxa- 1,3-dipolarꢀ speciesꢀ attacksꢀ β-carbonꢀ ofꢀ α,β-unsaturatedꢀ sys-
diazoles show antiallergic,10) antiviral,11)ꢀ anti-inflammatory,12) tems followed by isomerization.29) In fact the cycloaddition of
anticancer13) and antimicrobial14–19) activities. Additionally, nitrile imine generated from benzaldehyde phenylhydrazone
pyrazole and their derivatives exhibit remarkable pharmaco- inꢀ theꢀ presenceꢀ ofꢀ chloramine-Tꢀ toꢀ compoundꢀ 3 proceeded
logical activities such as antimicrobial, hypoglycemic, hyper- regioselectivelyꢀ withꢀ theꢀ formationꢀ ofꢀ 2-((arylaminosulfonyl)-
lipidemia,ꢀ andꢀ anti-inflammatory.20–24) The isoxazole nucleus methyl)-5-((4′,5′-dihydro-1′,3′-diphenyl-5′-aryl-1′H-pyrazol-4′-
is well known for its commercial application in various realms ylsulfonyl)ꢀmethyl)-1,3,4-oxadiazoleꢀ (4). The 1H-NMRꢀ spec-
of therapy, including cytotoxic agents.25) The marketed drugs trum of 4a displayed two doublets at δ 5.10 (C4′-H),ꢀ 5.34ꢀ
containing isoxazole moiety viz.,ꢀ acetylsulfisoxazole,ꢀ cyclo- (C5′-H)ꢀppm,ꢀtwoꢀsingletsꢀatꢀ4.72ꢀ(CH2-(C-5)),ꢀ5.13ꢀ(CH2-(C-2))ꢀ
serine,ꢀ drazoxol,ꢀ sulfisoxazoleꢀ andꢀ zonisamideꢀ haveꢀ aꢀ greatꢀ ppm and a broad singlet at 10.47ppm (NH). The signal due to
medicinal value. Recently, we have studied the antioxidant NH disappeared when D2O was added. In a much similar way,
properties of arylsulfonylaminosulfonylmethyl oxadiazoles, the cycloaddition of nitrile oxide generated from benzaldox-
pyrazolyl/isoxazolyl-oxadiazoles.26) Fascinated by diverse imeꢀinꢀtheꢀpresenceꢀofꢀchloramine-Tꢀtoꢀcompoundꢀ3 furnished
bioactivity of these heterocycles and in continuation of our 2-((arylaminosulfonyl)ꢀmethyl)-5-((4′,5′-dihydro-3′-phenyl-5′-
ongoing program26–28)ꢀ aimingꢀ atꢀ findingꢀ aꢀ newꢀ classꢀ ofꢀ bisꢀ arylisoxazol-4′-ylsulfonyl)ꢀmethyl)-1,3,4-oxadiazoleꢀ (5). The
heterocycles with potential chemotherapeutic activities, we addition of nitrile imines and nitrile oxides to 3 may lead to
planned to synthesize and to study the antioxidant property of isomers. The other isomer if any formed during the course
hithertoꢀ notꢀ reportedꢀ styrylsulfonylmethylꢀ 1,3,4-oxadiazolesꢀ of the reaction was not isolated. However, only one pure
andꢀpyrazolyl/isoxazolyl-1,3,4-oxadiazoles.
regioisomer was isolated under the applied reaction condi-
tions. This may be due to more electron withdrawing effect of
1
sulfonyl group.30) The H-NMRꢀ spectrumꢀ ofꢀ 5a showed two
Results and Discussion
Chemistryꢀ ꢀInitially,ꢀ 2-(arylaminosulfonylmethyl)-5-[Z- doublets at δ 5.18 and 5.43ppm due to C4′-Hꢀ andꢀ C5′-H.ꢀ Twoꢀ
(styrylsulfonylmethyl)]-1,3,4-oxadiazoleꢀ (3) was prepared by singlets were observed at 5.20 and 4.89ppm due to methylene
the cyclocondensation of arylaminosulfonylacetic acid hydra- protonsꢀattachedꢀtoꢀC-2ꢀandꢀC-5.ꢀTheꢀcompoundꢀ5a displayed
zide (1) with Z-styrylsulfonylaceticꢀ acidꢀ (2) in the presence a broad singlet at 10.52ppm due to NH which disappeared
1
of POCl3 (Chart 1). The H-NMRꢀ spectrumꢀ ofꢀ 3a displayed when D2O was added. The oxidation of pyrazoline and isoxa-
two singlets at δ 5.11 and 4.86ppm due to methylene protons zoline rings present in compounds 4 and 5 was performed
attachedꢀtoꢀC-2ꢀandꢀC-5.ꢀAꢀdoubletꢀwasꢀobservedꢀatꢀ6.59ꢀppmꢀ with chloranil in xylene to obtain the aromatized com-
dueꢀtoꢀtheꢀolefinꢀprotonꢀHB,ꢀwhileꢀtheꢀotherꢀolefinꢀprotonꢀHA poundsꢀ
2-((arylaminosulfonyl)ꢀmethyl)-5-((1′,3′-diphenyl-5′-
exhibitedꢀaꢀdoubletꢀatꢀmuchꢀdownfieldꢀregionꢀandꢀmergedꢀwithꢀ aryl-1′H-pyrazol-4′-ylsulfonyl)ꢀmethyl)-1,3,4-oxadiazoleꢀ(6) and
aromatic protons. The coupling constant value JAB=9.5Hz in- 2-((arylaminosulfonyl)ꢀmethyl)-5-((3′-phenyl-5′-arylisoxazol-4′-
dicated that they possess cis geometry. Further, a broad singlet ylsulfonyl)ꢀmethyl)-1,3,4-oxadiazoleꢀ (7). In the 1H-NMRꢀ
was appeared at 10.31ppm due to NH which disappeared on spectra of 6 and 7 the absence of signals corresponding to
deuteration.ꢀ Theꢀ 1,3-dipolarꢀ cycloadditionꢀ ofꢀ dipolarꢀ reagentsꢀ pyrazoline and isoxazoline ring protons indicated their forma-
to dipolarophiles was one of the facile techniques to prepare tion. The structures of 4–7 were further ascertained by IR and
five-memberedꢀ heterocycles.ꢀ Adoptingꢀ thisꢀ methodology,ꢀ theꢀ 13C-NMRꢀspectra.
Antioxidant Activity The compounds 3–7 were tested for
antioxidantꢀ propertyꢀ byꢀ 2,2,-diphenyl-1-picrylhydrazylꢀ radi-
Theꢀauthorsꢀdeclareꢀnoꢀconflictꢀofꢀinterest.
© 2013 The Pharmaceutical Society of Japan
*ꢀToꢀwhomꢀcorrespondenceꢀshouldꢀbeꢀaddressed.ꢀ e-mail:ꢀadivireddyp@yahoo.co.in

1292
Vol. 61, No. 12
Chart 1
Table 2. The in Vitro Antioxidant Activity of 3–7 in NO Method
Table 1. The in Vitro Antioxidant Activity of 3–7 in DPPH Method
Concentration
Compound
Concentration
Compound
50µg/mL (%)
75µg/mL (%)
100µg/mL (%)
50µg/mL (%)
75µg/mL (%)
100µg/mL (%)
3a
74.61 0.21
78.23 0.65
57.46 0.01
—
77.22 0.06
81.35 1.04
61.54 0.50
—
79.19 0.58
84.46 0.33
63.82 0.29
—
3a
73.10 0.03
77.21 1.45
56.92 0.38
—
73.43 0.50
78.67 0.79
60.76 0.42
—
75.25 0.21
82.35 1.03
63.23 0.61
—
3b
3b
3c
3c
4a
4a
4b
45.11 0.98
—
48.29 1.24
—
51.31 1.04
—
4b
41.57 0.15
—
44.40 0.65
—
46.24 0.41
—
4c
4c
5a
—
—
—
5a
—
—
—
5b
46.51 0.52
—
49.15 0.37
—
52.45 0.14
—
5b
44.71 1.19
—
48.26 0.32
—
51.42 0.45
—
5c
5c
6a
68.08 1.58
73.14 0.41
52.86 0.25
70.41 0.71
75.95 1.42
55.16 1.05
77.15 0.45
—
72.52 1.74
76.06 0.57
56.36 1.07
73.61 0.39
77.67 0.91
58.23 0.58
80.95 0.39
—
74.09 1.85
78.78 0.82
59.27 0.09
75.50 1.34
80.37 1.17
62.52 1.26
83.82 0.81
—
6a
66.12 0.11
71.75 1.44
50.92 0.09
68.81 1.92
73.23 1.47
54.20 1.55
78.23 0.17
—
70.57 0.60
74.13 1.29
55.19 0.85
71.21 1.68
75.35 1.22
56.37 1.45
81.46 1.37
—
72.42 0.73
76.26 1.51
57.72 0.65
74.97 1.45
78.96 0.96
60.11 1.86
82.79 0.80
—
6b
6b
6c
6c
7a
7b
7a
7b
7c
7c
Ascorbic acid
Blank
Ascorbic acid
Blank
(—)ꢀ Showedꢀ noꢀ scavengingꢀ activity.ꢀ Valuesꢀ wereꢀ theꢀ meansꢀ ofꢀ threeꢀ repli-
cate S.D.
(—)ꢀ Showedꢀ noꢀ scavengingꢀ activity.ꢀ Valuesꢀ wereꢀ theꢀ meansꢀ ofꢀ threeꢀ repli-
cates S.D.
cal (DPPH),31,32) nitric oxide (NO)33,34) and hydrogen peroxide moiety. In fact, the methyl substituted styrylsulfonylmethyl
(H2O2)35) methods. The results of the antioxidant activity of oxadiazole 3b displayed slightly higher radical scavenging ac-
test compounds and control drug are presented in Tables 1–3 tivity when compared with the standard ascorbic acid. Further,
and Figs. 1–3. The aim of this study was to identify the poten- it was observed that amongst bis heterocyclic compounds, the
tial pharmacophoric unit for antioxidant property. Amongst all aromatized compounds 6 and 7 displayed greater activity than
the compounds the mono heterocyclic derivatives, styrylsulfo- the respective dihydro derivatives 4 and 5. In fact, isoxazolyl
nylmethylꢀ1,3,4-oxadiazolesꢀ3 showed greater radical scaveng- oxadiazoles showed comparatively higher radical scavenging
ing activity than the bis heterocyclic compounds. This may activity than the pyrazolyl oxadiazoles. It was also noticed
be due to the presence of more electron withdrawing styryl that unsubstituted and methyl substituted compounds 3a, 3b,

December 2013
1293
Fig. 1. The in Vitro Antioxidant Activity of Compounds 3–7 in DPPH Method
Table 3. The in Vitro Antioxidant Activity of 3–7 in H2O2 Method
Concentration
Compound
50µg/mL (%)
75µg/mL (%)
100µg/mL (%)
3a
72.12 0.53
76.51 0.15
58.31 1.25
—
75.24 0.17
78.79 0.07
60.05 1.16
—
78.40 0.37
81.44 0.45
64.89 1.72
—
3b
3c
4a
4b
43.28 0.41
—
46.61 0.88
—
48.11 0.73
—
4c
5a
—
—
—
5b
45.82 1.41
—
47.57 1.12
—
50.27 1.33
—
5c
6a
66.19 1.04
71.56 0.33
53.74 1.36
69.27 0.21
72.54 1.69
56.06 0.62
77.68 0.51
—
70.39 0.92
75.14 0.10
55.65 0.94
73.49 0.58
76.43 1.45
59.91 0.49
79.27 1.29
—
74.65 0.69
77.21 0.82
58.62 1.29
76.68 0.51
79.77 1.81
62.54 0.71
83.16 0.44
—
Fig. 2. The in Vitro Antioxidant Activity of Compounds 3–7 in NO
Method
6b
6c
7a
7b
Experimental
General Melting points were determined in open capillar-
iesꢀonꢀaꢀMel-Tempꢀapparatusꢀandꢀareꢀuncorrected.ꢀTheꢀpurityꢀ
of the compounds was checked by TLC (silica gel H, BDH,
hexane–ethylꢀacetate,ꢀ3ꢀ:ꢀ1).ꢀTheꢀIRꢀspectraꢀwereꢀrecordedꢀonꢀaꢀ
ThermoꢀNicoletꢀIRꢀ200ꢀFT-IRꢀspectrometerꢀasꢀKBrꢀpelletsꢀandꢀ
7c
Ascorbic acid
Blank
(—)ꢀ Showedꢀ noꢀ scavengingꢀ activity.ꢀ Valuesꢀ wereꢀ theꢀ meansꢀ ofꢀ threeꢀ repli-
cates S.D.
1
the wave numbers were given in cm−1. The H-NMRꢀ spectraꢀ
wereꢀ recordedꢀ inꢀ DMSO-d6 on a Jeol JNM λ-400ꢀMHz.ꢀ Theꢀ
6a, 6b, 7a and 7b exhibited higher activity than the corre- 13C-NMRꢀspectraꢀwereꢀrecordedꢀinꢀDMSO-d6 on a Jeol JNM
sponding chloro substituted compounds 3c, 6c and 7c. The spectrometer operating at 100MHz. All chemical shifts are
compounds 4b and 5b exhibited low activity while 4a, 4c, reported in δ (ppm) using tetramethylsilane (TMS) as an in-
5a and 5c showed no activity. Besides, the perusal of Tables ternal standard. The antioxidant property was carried out by
1–3 indicated that radical scavenging activity increases with usingꢀShimadzuꢀUV-2450ꢀspectrophotometer.ꢀTheꢀmassꢀspec-
increase in concentration in all the three methods.
traꢀwereꢀrecordedꢀonꢀJeolꢀJMS-Dꢀ300ꢀandꢀFinniganꢀMatꢀ1210ꢀ
B at 70eV with an emission current of 100µA. The elemental
analysesꢀwereꢀdeterminedꢀusingꢀPerkin-Elmerꢀ240Cꢀelementalꢀ
Conclusion
Aꢀvarietyꢀofꢀmonoꢀandꢀbisꢀheterocycles-styrylsulfonylmeth- analyzer. The arylaminosulfonylacetic acid hydrazide (1) and
ylꢀ 1,3,4-oxadiazoles,ꢀ pyrazolyl/isoxazolyl-1,3,4-oxadiazolesꢀ Z-styrylsulfonylaceticꢀacidꢀ(2) were prepared as per the litera-
were prepared from arylaminosulfonylacetic acid hydrazide ture procedure.27,36,37)
and Z-styrylsulfonylaceticꢀ acidꢀ andꢀ studiedꢀ theirꢀ antioxidantꢀ
General Procedure for the Synthesis of 2-(Aryl-
activity.ꢀ Theꢀ styrylsulfonylmethylꢀ 1,3,4-oxadiazoles,ꢀ pyr- aminosulfonylmethyl)-5-[Z-(styrylsulfonylmethyl)]-1,3,4-
azolyl/isoxazolyl-1,3,4-oxadiazolesꢀ wereꢀ displayedꢀ greaterꢀ oxadiazole (3a–c) To an equimolar mixture (10mmol) of
antioxidantꢀ activityꢀ thanꢀ theꢀ pyrazolinyl/isoxazolinyl-1,3,4- arylaminosulfonylacetic acid hydrazide (1) and Z-styrylsulfo-
oxadiazoles. In fact, the methyl substituted compound 3b nylacetic acid (2), POCl3 (7mL) was added and heated under
showed slightly higher antioxidant activity than the standard refluxꢀforꢀ3–5ꢀh.ꢀTheꢀexcessꢀPOCl3 was removed in vacuo and
ascorbic acid.
the residue was poured onto crushed ice. The resulting pre-
cipitateꢀwasꢀfiltered,ꢀwashedꢀwithꢀsaturatedꢀsodiumꢀbicarbon-

1294
Vol. 61, No. 12
Fig. 3. The in Vitro Antioxidant Activity of Compounds 3–7 in H2O2 Method
ate solution followed by water. It was dried and recrystallized solvent was removed under vacuum. The resultant residue was
from ethanol. purifiedꢀbyꢀcolumnꢀchromatographyꢀ(silicaꢀgel,ꢀ60–120ꢀmesh)ꢀ
2-(Phenylaminosulfonylmethyl)-5-[Z-(styrylsulfonyl- usingꢀhexane–ethylꢀacetateꢀ(4ꢀ:ꢀ1)ꢀasꢀeluent.
methyl)]-1,3,4-oxadiazoleꢀ (3a):ꢀ Whiteꢀ solid,ꢀ yieldꢀ 67%,ꢀ mpꢀ
2-((Phenylaminosulfonyl)ꢀmethyl)-5-((4′,5′-dihydro-1′,3′-
122–124°C. IR (KBr) cm−1:ꢀ 1160,ꢀ 1315ꢀ (SO2), 1572 (C= diphenyl-5′-phenyl-1′H-pyrazol-4′-ylsulfonyl)ꢀmethyl)-1,3,4-
N), 1625 (C=C), 3227 (NH). 1H-NMRꢀ (DMSO-d6) δ:ꢀ 4.86ꢀ oxadiazole (4a):ꢀPaleꢀyellowꢀsolid,ꢀyieldꢀ70%,ꢀmpꢀ162–164°C.ꢀ
(s, 2H, CH2-(C-5)),ꢀ 5.11ꢀ (s,ꢀ 2H,ꢀ CH2-(C-2)),ꢀ 6.59ꢀ (d,ꢀ 1H,ꢀ HB, IR (KBr) cm−1:ꢀ 1132,ꢀ 1327ꢀ (SO2), 1575 (C=N), 3248 (NH).
J=9.5Hz), 7.11–7.69 (m, 11H, HA,ꢀAr-H),ꢀ10.31ꢀ(brꢀs,ꢀ1H,ꢀNH).ꢀ 1H-NMRꢀ (DMSO-d6) δ:ꢀ 4.72ꢀ (s,ꢀ 2H,ꢀ CH2-(C-5)),ꢀ 5.10ꢀ (d,ꢀ 1H,ꢀ
13C-NMRꢀ (DMSO-d6) δ:ꢀ 44.3ꢀ (CH2-(C-5)),ꢀ 49.7ꢀ (CH2-(C-2)),ꢀ C4′-H,ꢀ J=7.1Hz), 5.13 (s, 2H, CH2-(C-2)),ꢀ 5.34ꢀ (d,ꢀ 1H,ꢀ C5′-H,ꢀ
121.6ꢀ (C-HB),ꢀ 140.2ꢀ (C-HA),ꢀ 157.3ꢀ (C-5),ꢀ 158.2ꢀ (C-2),ꢀ 124.7,ꢀ J=7.1ꢀHz),ꢀ 7.21–7.69ꢀ (m,ꢀ 20H,ꢀ Ar-H),ꢀ 10.47ꢀ (brꢀs,ꢀ 1H,ꢀ NH).ꢀ
125.6, 126.4, 128.3, 128.9, 129.4, 130.2, 131.1 (aromatic car- 13C-NMRꢀ (DMSO-d6) δ:ꢀ 47.6ꢀ (CH2-(C-5)),ꢀ 51.5ꢀ (CH2-(C-2)),ꢀ
bons). MS m/z:ꢀ419.47ꢀ(M+). Anal. Calcd for C18H17N3O5S2:ꢀC,ꢀ 65.8ꢀ (C-5′),ꢀ84.5ꢀ(C-4′),ꢀ154.5ꢀ(C-3′),ꢀ157.7ꢀ(C-5),ꢀ158.5ꢀ(C-2),ꢀ
51.54;ꢀH,ꢀ4.08;ꢀN,ꢀ10.02.ꢀFound:ꢀC,ꢀ51.60;ꢀH,ꢀ4.10;ꢀN,ꢀ10.12.
124.6, 125.3, 126.7, 127.1, 128.1, 129.2, 130.6, 131.5, 132.7,
2-(p-Methylphenylaminosulfonylmethyl)-5-[Z-(p-methyl- 133.8, 134.2, 135.1 (aromatic carbons). MS m/z:ꢀ 613.71ꢀ (M+).
styrylsulfonylmethyl)]-1,3,4-oxadiazoleꢀ(3b):ꢀWhiteꢀsolid,ꢀyieldꢀ Anal. Calcd for C31H27N5O5S2:ꢀ C,ꢀ 60.67;ꢀ H,ꢀ 4.43;ꢀ N,ꢀ 11.41.ꢀ
65%, mp 101–103°C. IR (KBr) cm−1:ꢀ 1155,ꢀ 1312ꢀ (SO2), 1565 Found:ꢀC,ꢀ60.82;ꢀH,ꢀ4.57;ꢀN,ꢀ11.65.
1
(C=N), 1622 (C=C), 3224 (NH). H-NMRꢀ(DMSO-d6) δ:ꢀ2.21ꢀ
2-(( p-Methylphenylaminosulfonyl)ꢀmethyl)-5-((4′,5′-
andꢀ2.27ꢀ(s,ꢀ6H,ꢀAr-CH3), 4.69 (s, 2H, CH2-(C-5)),ꢀ5.06ꢀ(s,ꢀ2H,ꢀ dihydro-1′,3′-diphenyl-5′-(p-methylphenyl)-1′H-pyrazol-4′-
CH2-(C-2)),ꢀ6.42ꢀ(d,ꢀ1H,ꢀHB, J=9.3Hz), 7.03–7.59 (m, 9H, HA, ylsulfonyl)ꢀmethyl)-1,3,4-oxadiazoleꢀ (4b):ꢀ Paleꢀ yellowꢀ solid,ꢀ
Ar-H),ꢀ 10.02ꢀ (brꢀs,ꢀ 1H,ꢀ NH).ꢀ 13C-NMRꢀ (DMSO-d6) δ:ꢀ 21.2ꢀ yield 68%, mp 156–158°C. IR (KBr) cm−1:ꢀ 1128,ꢀ 1321ꢀ (SO2),
1
andꢀ 21.9ꢀ (Ar-CH3), 42.8 (CH2-(C-5)),ꢀ 48.4ꢀ (CH2-(C-2)),ꢀ 120.8ꢀ 1566 (C=N), 3240 (NH). H-NMRꢀ (DMSO-d6) δ:ꢀ 2.24ꢀ andꢀ
(C-HB),ꢀ 137.1ꢀ (C-HA),ꢀ 154.5ꢀ (C-5),ꢀ 155.1ꢀ (C-2),ꢀ 122.5,ꢀ 123.7,ꢀ 2.37ꢀ (s,ꢀ 6H,ꢀ Ar-CH3), 4.52 (s, 2H, CH2-(C-5)),ꢀ 5.04ꢀ (d,ꢀ 1H,ꢀ
124.4, 124.9, 127.1, 127.9, 129.5, 130.6 (aromatic carbons). MS C4′-H,ꢀ J=6.9Hz), 5.11 (s, 2H, CH2-(C-2)),ꢀ 5.30ꢀ (d,ꢀ 1H,ꢀ C5′-H,ꢀ
m/z:ꢀ447.53ꢀ(M+). Anal. Calcd for C20H21N3O5S2:ꢀC,ꢀ53.68;ꢀH,ꢀ J=6.9ꢀHz),ꢀ 7.15–7.52ꢀ (m,ꢀ 18H,ꢀ Ar-H),ꢀ 10.35ꢀ (brꢀs,ꢀ 1H,ꢀ NH).ꢀ
4.73;ꢀN,ꢀ9.39.ꢀFound:ꢀC,ꢀ53.63;ꢀH,ꢀ4.72;ꢀN,ꢀ9.47.
13C-NMRꢀ (DMSO-d6) δ:ꢀ 21.7ꢀ andꢀ 22.5ꢀ (Ar-CH3), 46.3 (CH2-
2-(p-Chlorophenylaminosulfonylmethyl)-5-[Z-(p-chloro- (C-5)),ꢀ 52.7ꢀ (CH2-(C-2)),ꢀ 64.9ꢀ (C-5′),ꢀ83.1ꢀ(C-4′),ꢀ153.1ꢀ(C-3′),
styrylsulfonylmethyl)]-1,3,4-oxadiazoleꢀ(3c):ꢀWhiteꢀsolid,ꢀyieldꢀ 156.5ꢀ (C-5),ꢀ 157.2ꢀ (C-2),ꢀ 123.3,ꢀ 124.2,ꢀ 125.5,ꢀ 126.5,ꢀ 127.1,ꢀ
69%, mp 140–142°C. IR (KBr) cm−1:ꢀ 1169,ꢀ 1318ꢀ (SO2), 1580 127.9, 129.7, 130.5, 131.4, 133.2, 133.9, 134.5 (aromatic car-
1
(C=N), 1630 (C=C), 3235 (NH). H-NMRꢀ(DMSO-d6) δ:ꢀ5.02ꢀ bons). MS m/z:ꢀ641.76ꢀ(M+). Anal. Calcd for C33H31N5O5S2:ꢀC,ꢀ
(s, 2H, CH2-(C-5)),ꢀ 5.25ꢀ (s,ꢀ 2H,ꢀ CH2-(C-2)),ꢀ 6.87ꢀ (d,ꢀ 1H,ꢀ HB, 61.76;ꢀH,ꢀ4.86;ꢀN,ꢀ10.91.ꢀFound:ꢀC,ꢀ61.83;ꢀH,ꢀ5.02;ꢀN,ꢀ10.99.
J=9.8Hz), 7.17–7.71 (m, 9H, HA,ꢀAr-H),ꢀ10.45ꢀ(brꢀs,ꢀ1H,ꢀNH).ꢀ
2-(( p-Chlorophenylaminosulfonyl)ꢀmethyl)-5-((4′,5′-
13C-NMRꢀ (DMSO-d6) δ:ꢀ 47.6ꢀ (CH2-(C-5)),ꢀ 50.9ꢀ (CH2-(C-2)),ꢀ dihydro-1′,3′-diphenyl-5′-(p-chlorophenyl)-1′H-pyrazol-4′-
122.5ꢀ (C-HB),ꢀ 143.1ꢀ (C-HA),ꢀ 158.1ꢀ (C-5),ꢀ 159.7ꢀ (C-2),ꢀ 127.7,ꢀ ylsulfonyl)ꢀmethyl)-1,3,4-oxadiazoleꢀ (4c):ꢀ Paleꢀ yellowꢀ solid,ꢀ
128.6, 129.0, 129.7, 130.5, 131.2, 132.6, 133.4 (aromatic car- yield 74%, mp 177–179°C. IR (KBr) cm−1:ꢀ 1135,ꢀ 1337ꢀ (SO2),
bons). MS m/z:ꢀ488.36ꢀ(M+). Anal. Calcd for C18H15 Cl2N3O5S2:ꢀ 1578 (C=N), 3252 (NH). H-NMRꢀ(DMSO-d6) δ:ꢀ4.84ꢀ(s,ꢀ2H,ꢀ
C,ꢀ44.27;ꢀH,ꢀ3.10;ꢀN,ꢀ8.60.ꢀFound:ꢀC,ꢀ44.22;ꢀH,ꢀ3.07;ꢀN,ꢀ8.56.
1
CH2-(C-5)),ꢀ 5.16ꢀ (d,ꢀ 1H,ꢀ C4′-H,ꢀ J=7.4Hz), 5.15 (s, 2H, CH2-
General Procedure for the Synthesis 2-((Arylaminosulfo- (C-2)),ꢀ5.35ꢀ(d,ꢀ1H,ꢀC5′-H,ꢀJ=7.4ꢀHz),ꢀ7.29–7.74ꢀ(m,ꢀ18H,ꢀAr-H),ꢀ
nyl)methyl)-5-((4′,5′-sssdihydro-1′,3′-diphenyl-5′-aryl-1′H- 10.54 (brs, 1H, NH). 13C-NMRꢀ (DMSO-d6) δ:ꢀ 48.7ꢀ (CH2-
pyrazol-4′-ylsulfonyl)methyl)-1,3,4-oxadiazole (4a–c) The (C-5)),ꢀ 53.2ꢀ (CH2-(C-2)),ꢀ 67.9ꢀ (C-5′),ꢀ85.8ꢀ (C-4′),ꢀ155.9ꢀ (C-3′),
compound
3
(1mmol), benzaldehyde phenylhydrazone 158.4ꢀ (C-5),ꢀ 159.6ꢀ (C-2),ꢀ 125.4,ꢀ 126.2,ꢀ 127.2,ꢀ 128.2,ꢀ 129.8,ꢀ
(1.2ꢀmmol),ꢀ andꢀ chloramine-Tꢀ (1.2ꢀmmol)ꢀ andꢀ methanolꢀ 130.6, 131.4, 132.7, 133.5, 134.2, 135.1, 136.3 (aromatic car-
(20ꢀmL)ꢀ wereꢀ refluxedꢀ forꢀ 17–20ꢀh.ꢀ Theꢀ precipitatedꢀ inorganicꢀ bons). MS m/z:ꢀ682.61ꢀ(M+). Anal. Calcd. for C31H25Cl2N5O5S2:ꢀ
saltsꢀ wereꢀ filteredꢀ off.ꢀ Theꢀ filtrateꢀ wasꢀ concentratedꢀ andꢀ theꢀ C,ꢀ54.54;ꢀH,ꢀ3.69;ꢀN,ꢀ10.25.ꢀFound:ꢀC,ꢀ54.27;ꢀH,ꢀ3.82;ꢀN,ꢀ9.89.
residue was extracted with dichloromethane. The organic layer
General Procedure for the Synthesis of 2-((Aryl-
was washed with water, brine and dried (an. Na2SO4). The aminosulfonyl)methyl)-5-((4′,5′-dihydro-3′-phenyl-5′-

December 2013
1295
arylisoxazol-4′-ylsulfonyl)methyl)-1,3,4-oxadiazole (5a–c) phenyl-1′H-pyrazol-4′-ylsulfonyl)ꢀmethyl)-1,3,4-oxadiazoleꢀ
A mixture of compound 3 (1mmol), benzaldoxime (1.2mmol), (6a):ꢀWhiteꢀsolid,ꢀyieldꢀ62%,ꢀmpꢀ180–182°C.ꢀIRꢀ(KBr)ꢀcm−1:ꢀ
chloramine-Tꢀ (1.2ꢀmmol)ꢀ andꢀ methanolꢀ (20ꢀmL)ꢀ wasꢀ refluxedꢀ 1125, 1329 (SO2), 1562 (C=N), 1627 (C=C), 3260 (NH).
forꢀ14–17ꢀh.ꢀTheꢀprecipitatedꢀinorganicꢀsaltsꢀwereꢀfilteredꢀoff.ꢀ 1H-NMRꢀ (DMSO-d6) δ:ꢀ 5.09ꢀ (s,ꢀ 2H,ꢀ CH2-(C-5)),ꢀ 5.30ꢀ (s,ꢀ 2H,ꢀ
Theꢀ filtrateꢀ wasꢀ concentratedꢀ andꢀ theꢀ residueꢀ wasꢀ extractedꢀ CH2-(C-2)),ꢀ 7.06–7.71ꢀ (m,ꢀ 20H,ꢀ Ar-H),ꢀ 10.55ꢀ (brꢀs,ꢀ 1H,ꢀ NH).ꢀ
with dichloromethane. The organic layer was washed with 13C-NMRꢀ (DMSO-d6) δ:ꢀ 45.6ꢀ (CH2-(C-5)),ꢀ 50.2ꢀ (CH2-(C-2)),ꢀ
water, brine and dried (an. Na2SO4).ꢀ Evaporationꢀ ofꢀ theꢀ sol- 136.9ꢀ (C-4′),ꢀ 146.2ꢀ (C-3′),ꢀ 149.7ꢀ (C-5′),ꢀ 157.5ꢀ (C-5),ꢀ 158.3ꢀ
vent under reduced pressure yielded a solid which was puri- (C-2),ꢀ 123.3,ꢀ 123.6,ꢀ 124.1,ꢀ 124.9,ꢀ 126.6,ꢀ 127.4,ꢀ 128.2,ꢀ 129.5,ꢀ
fiedꢀ byꢀ columnꢀ chromatographyꢀ (silicaꢀ gel,ꢀ 60–120ꢀ mesh)ꢀ 130.1, 131.7, 132.4, 133.5 (aromatic carbons). MS m/z:ꢀ 611.70ꢀ
usingꢀhexane–ethylꢀacetateꢀ(4ꢀ:ꢀ1)ꢀasꢀeluent.
2-((Phenylaminosulfonyl)ꢀmethyl)-5-((4′,5′-dihydro-3′- 11.45.ꢀFound:ꢀC,ꢀ61.25;ꢀH,ꢀ4.31;ꢀN,ꢀ11.69.
(M+). Anal. Calcd for C31H25N5O5S2:ꢀ C,ꢀ 60.86;ꢀ H,ꢀ 4.12;ꢀ N,ꢀ
phenyl-5′-phenylisoxazol-4′-ylsulfonyl)mꢀ ethyl)-1,3,4-
2-(( p-Methylphenylaminosulfonyl)ꢀmethyl)-5-((1′,3′-
oxadiazoles (5a):ꢀ Whiteꢀ solid,ꢀ yieldꢀ 67%,ꢀ mpꢀ 149–151°C.ꢀ diphenyl-5′-(p-methylphenyl)-1′H-pyrazol-4′-ylsulfonyl)-
IR (KBr) cm−1:ꢀ 1140,ꢀ 1330ꢀ (SO2), 1560 (C=N), 3237 (NH). methyl)-1,3,4-oxadiazoleꢀ (6b):ꢀ Whiteꢀ solid,ꢀ yieldꢀ 66%,ꢀ mpꢀ
1H-NMRꢀ (DMSO-d6) δ:ꢀ 4.89ꢀ (s,ꢀ 2H,ꢀ CH2-(C-5)),ꢀ 5.18ꢀ (d,ꢀ 1H,ꢀ 168–170°C. IR (KBr) cm−1:ꢀ 1130,ꢀ 1335ꢀ (SO2), 1570 (C=N),
1
C4′-H,ꢀ J=7.6Hz), 5.20 (s, 2H, CH2-(C-2)),ꢀ 5.43ꢀ (d,ꢀ 1H,ꢀ C5′-H,ꢀ 1624 (C=C), 3265 (NH). H-NMRꢀ (DMSO-d6) δ:ꢀ 2.26ꢀ andꢀ
J=7.6ꢀHz),ꢀ 7.31–7.85ꢀ (m,ꢀ 15H,ꢀ Ar-H),ꢀ 10.50ꢀ (brꢀs,ꢀ 1H,ꢀ NH).ꢀ 2.39ꢀ (s,ꢀ 6H,ꢀ Ar-CH3), 5.03 (s, 2H, CH2-(C-5)),ꢀ 5.28ꢀ (s,ꢀ 2H,ꢀ
13C-NMRꢀ (DMSO-d6) δ:ꢀ 48.6ꢀ (CH2-(C-5)),ꢀ 53.4ꢀ (CH2-(C-2)),ꢀ CH2-(C-2)),ꢀ 6.94–7.52ꢀ (m,ꢀ 18H,ꢀ Ar-H),ꢀ 10.50ꢀ (brꢀs,ꢀ 1H,ꢀ NH).ꢀ
64.5ꢀ (C-4′),ꢀ85.3ꢀ(C-5′),ꢀ155.2ꢀ(C-3′),ꢀ158.1ꢀ(C-5),ꢀ158.9ꢀ(C-2),ꢀ 13C-NMRꢀ (DMSO-d6) δ:ꢀ 21.5ꢀ andꢀ 22.4ꢀ (Ar-CH3), 45.8 (CH2-
125.7, 126.1, 127.3, 129.5, 130.6, 131.4, 132.1, 135.7 (aromatic (C-5)),ꢀ 49.9ꢀ (CH2-(C-2)),ꢀ 136.3ꢀ (C-4′),ꢀ 145.9ꢀ (C-3′), 148.7
carbons). MS m/z:ꢀ538.64ꢀ(M+). Anal. Calcd for C25H22N4O6S2:ꢀ (C-5′),ꢀ 156.6ꢀ (C-5),ꢀ 157.6ꢀ (C-2),ꢀ 122.7,ꢀ 123.1,ꢀ 123.9,ꢀ 124.8,ꢀ
C,ꢀ55.74;ꢀH,ꢀ4.11;ꢀN,ꢀ10.40.ꢀFound:ꢀC,ꢀ56.03;ꢀH,ꢀ4.29;ꢀN,ꢀ10.47. 124.9, 126.8, 127.5, 128.6, 129.7, 130.3, 131.6, 134.1 (aromatic
2-(( p-Methylphenylaminosulfonyl)ꢀmethyl)-5-((4′,5′- carbons). MS m/z:ꢀ639.76ꢀ(M+). Anal. Calcd for C33H29N5O5S2:ꢀ
dihydro-3′-phenyl-5′-(p-methylphenyl)ꢀisoxazol-4′-ylsulfonyl)- C,ꢀ61.95;ꢀH,ꢀ4.56;ꢀN,ꢀ10.94.ꢀFound:ꢀC,ꢀ62.28;ꢀH,ꢀ4.93;ꢀN,ꢀ11.13.
methyl)-1,3,4-oxadiazolesꢀ (5b):ꢀ Whiteꢀ solid,ꢀ yieldꢀ 60%,ꢀ mpꢀ
2-(( p-Chlorophenylaminosulfonyl)ꢀmethyl)-5-((1′,3′-
129–131°C. IR (KBr) cm−1:ꢀ 1134,ꢀ 1324ꢀ (SO2), 1555 (C= diphenyl-5′-(p-chlorophenyl)-1′H-pyrazol-4'-ylsulfonyl)-
N), 3230 (NH). 1H-NMRꢀ (DMSO-d6) δ:ꢀ 2.28ꢀ andꢀ 2.42ꢀ (s,ꢀ methyl)-1,3,4-oxadiazoleꢀ (6c):ꢀ Whiteꢀ solid,ꢀ yieldꢀ 69%,ꢀ mpꢀ
6H,ꢀ Ar-CH3), 4.94 (s, 2H, CH2-(C-5)),ꢀ 5.12ꢀ (d,ꢀ 1H,ꢀ C4′-H,ꢀ 188–190°C. IR (KBr) cm−1:ꢀ 1137,ꢀ 1338ꢀ (SO2), 1575 (C=N),
J=7.2Hz), 5.14 (s, 2H, CH2-(C-2)),ꢀ 5.36ꢀ (d,ꢀ 1H,ꢀ C5′-H,ꢀ 1632 (C=C), 3272 (NH). 1H-NMRꢀ (DMSO-d6) δ:ꢀ 5.16ꢀ (s,ꢀ
J=7.2ꢀHz),ꢀ 7.21–7.72ꢀ (m,ꢀ 13H,ꢀ Ar-H),ꢀ 10.49ꢀ (brꢀs,ꢀ 1H,ꢀ NH).ꢀ 2H, CH2-(C-5)),ꢀ 5.39ꢀ (s,ꢀ 2H,ꢀ CH2-(C-2)),ꢀ 7.14–7.91ꢀ (m,ꢀ 18H,ꢀ
13C-NMRꢀ (DMSO-d6) δ:ꢀ 22.6ꢀ andꢀ 24.2ꢀ (Ar-CH3), 47.5 (CH2- Ar-H),ꢀ 10.64ꢀ (brꢀs,ꢀ 1H,ꢀ NH).ꢀ 13C-NMRꢀ (DMSO-d6) δ:ꢀ 46.8ꢀ
(C-5)),ꢀ 52.1ꢀ (CH2-(C-2)),ꢀ 62.9ꢀ (C-4′),ꢀ84.2ꢀ(C-5′),ꢀ153.3ꢀ(C-3′), (CH2-(C-5)),ꢀ 52.2ꢀ (CH2-(C-2)),ꢀ 137.5ꢀ (C-4′),ꢀ 147.3ꢀ (C-3′),
157.4ꢀ (C-5),ꢀ 158.1ꢀ (C-2),ꢀ 124.5,ꢀ 125.2,ꢀ 127.6,ꢀ 128.4ꢀ 129.3,ꢀ 150.2ꢀ (C-5′),ꢀ 157.5ꢀ (C-5),ꢀ 158.9ꢀ (C-2),ꢀ 124.3,ꢀ 124.6,ꢀ 125.9,ꢀ
130.6, 133.2, 134.8 (aromatic carbons). MS m/z:ꢀ 566.67ꢀ (M+). 126.3, 127.6, 128.5, 129.8, 130.5, 131.6, 132.3, 133.6, 134.7
Anal. Calcd for C27H26N4O6S2:ꢀ C,ꢀ 57.22;ꢀ H,ꢀ 4.62;ꢀ N,ꢀ 9.88.ꢀ (aromatic carbons). MS m/z:ꢀ 680.59ꢀ (M+). Anal. Calcd for
Found:ꢀC,ꢀ57.34;ꢀH,ꢀ4.90;ꢀN,ꢀ10.01.
C31H23Cl2N5O5S2:ꢀC,ꢀ54.70;ꢀH,ꢀ3.40;ꢀN,ꢀ10.28.ꢀFound:ꢀC,ꢀ54.79;ꢀ
2-(( p-Chlorophenylaminosulfonyl)ꢀmethyl)-5-((4′,5′- H, 3.65; N, 10.34.
dihydro-3′-phenyl-5′-(p-chlorophenyl)ꢀisoxazol-4′-ylsulfonyl)-
2-((Phenylaminosulfonyl)mꢀ ethyl)-5-((3′-phenyl-5′-
methyl)-1,3,4-oxadiazolesꢀ (5c):ꢀ Whiteꢀ solid,ꢀ yieldꢀ 73%,ꢀ mpꢀ phenylisoxazol-4′-ylsulfonyl)ꢀmethyl)-1,3,4-oxadiazoleꢀ
(7a):ꢀ
171–173°C. IR (KBr) cm−1:ꢀ 1146,ꢀ 1333ꢀ (SO2), 1564 (C=N), Whiteꢀsolid,ꢀyieldꢀ71%,ꢀmpꢀ153–155°C.ꢀIRꢀ(KBr)ꢀcm−1:ꢀ1120,ꢀ
1
1
3245 (NH). H-NMRꢀ (DMSO-d6) δ:ꢀ 4.99ꢀ (s,ꢀ 2H,ꢀ CH2-(C-5)),ꢀ 1323 (SO2), 1580 (C=N), 1620 (C=C), 3268 (NH). H-NMRꢀ
5.23 (d, 1H, C4′-H,ꢀJ=7.7Hz), 5.27 (s, 2H, CH2-(C-2)),ꢀ5.51ꢀ(d,ꢀ (DMSO-d6) δ:ꢀ5.26ꢀ(s,ꢀ2H,ꢀCH2-(C-5)),ꢀ5.41ꢀ(s,ꢀ2H,ꢀCH2-(C-2)),ꢀ
1H, C5′-H,ꢀ J=7.7ꢀHz),ꢀ 7.38–7.93ꢀ (m,ꢀ 13H,ꢀ Ar-H),ꢀ 10.59ꢀ (brꢀs,ꢀ 7.19–7.84ꢀ (m,ꢀ 15H,ꢀ Ar-H),ꢀ 10.57ꢀ (brꢀs,ꢀ 1H,ꢀ NH).ꢀ 13C-NMRꢀ
1H, NH). 13C-NMRꢀ (DMSO-d6) δ:ꢀ 49.5ꢀ (CH2-(C-5)),ꢀ 53.8ꢀ (DMSO-d6) δ:ꢀ47.1ꢀ(CH2-(C-5)),ꢀ51.5ꢀ(CH2-(C-2)),ꢀ138.2ꢀ(C-4′),
(CH2-(C-2)),ꢀ 61.4ꢀ (C-4′),ꢀ83.7ꢀ(C-5′),ꢀ152.8ꢀ(C-3′),ꢀ158.8ꢀ(C-5),ꢀ 147.3ꢀ(C-3′),ꢀ151.4ꢀ(C-5′),ꢀ157.9ꢀ(C-5),ꢀ158.5ꢀ(C-2),ꢀ125.1,ꢀ126.6,ꢀ
159.2ꢀ (C-2),ꢀ 123.7,ꢀ 125.8,ꢀ 126.9,ꢀ 127.5,ꢀ 128.8,ꢀ 130.1,ꢀ 131.9,ꢀ 127.1, 128.4, 129.2, 130.4, 131.8, 133.5 (aromatic carbons). MS
136.6 (aromatic carbons). MS m/z:ꢀ 607.51ꢀ (M+). Anal. Calcd m/z:ꢀ536.60ꢀ(M+). Anal. Calcd for C25H20N4O6S2:ꢀC,ꢀ55.95;ꢀH,ꢀ
for C25H20Cl2N4O6S2:ꢀ C,ꢀ 49.42;ꢀ H,ꢀ 3.31;ꢀ N,ꢀ 9.22.ꢀ Found:ꢀ C,ꢀ 3.75;ꢀN,ꢀ10.44.ꢀFound:ꢀC,ꢀ56.07;ꢀH,ꢀ3.84;ꢀN,ꢀ10.71.
49.15; H, 3.37; N, 9.08.
2-((p-Methylphenylaminosulfonyl)ꢀmethyl)-5-((3′-phenyl-5′-
General Procedure for the Synthesis of 2-((Aryl- ( p-methylphenyl)ꢀisoxazol-4′-ylsulfonyl)ꢀmethyl)-1,3,4-
aminosulfonyl)methyl)-5-((1′,3′-diphenyl-5′-aryl-1′H- oxadiazole (7b):ꢀ Whiteꢀ solid,ꢀ yieldꢀ 68%,ꢀ mpꢀ 141–143°C.ꢀ IRꢀ
pyrazol-4′-ylsulfonyl)methyl)-1,3,4-oxadiazole
(6a–c)/2- (KBr) cm−1:ꢀ1115,ꢀ1325ꢀ(SO2), 1583 (C=N), 1618 (C=C), 3264
1
((Arylaminosulfonyl)methyl)-5-((3′-phenyl-5′-aryl- (NH). H-NMRꢀ(DMSO-d6) δ:ꢀ2.30ꢀandꢀ2.45ꢀ(s,ꢀ6H,ꢀAr-CH3),
isoxazol-4′-ylsulfonyl)methyl)-1,3,4-oxadiazoles(7a–c) The 5.21 (s, 2H, CH2-(C-5)),ꢀ5.32ꢀ(s,ꢀ2H,ꢀCH2-(C-2)),ꢀ7.24–7.88ꢀ(m,ꢀ
compound 4/5 (1mmol), chloranil (1.2mmol) in xylene (10mL) 13H,ꢀ Ar-H),ꢀ 10.60ꢀ (brꢀs,ꢀ 1H,ꢀ NH).ꢀ 13C-NMRꢀ (DMSO-d6) δ:ꢀ
wasꢀrefluxedꢀforꢀ23–26ꢀh.ꢀThen,ꢀitꢀwasꢀtreatedꢀwithꢀ5%ꢀsodiumꢀ 22.4ꢀ andꢀ 23.1ꢀ (Ar-CH3), 46.4 (CH2-(C-5)),ꢀ 51.1ꢀ (CH2-(C-2)),ꢀ
hydroxide solution. The organic extract was separated, washed 137.5ꢀ (C-4′),ꢀ 146.5ꢀ (C-3′),ꢀ 150.4ꢀ (C-5′),ꢀ 157.2ꢀ (C-5),ꢀ 158.1ꢀ
with water and dried (an. Na2SO4). The solvent was removed (C-2),ꢀ 124.5,ꢀ 125.7,ꢀ 126.4,ꢀ 127.8,ꢀ 128.7,ꢀ 129.7,ꢀ 130.6,ꢀ 132.9ꢀ
under reduced pressure. The resultant solid was recrystallized (aromatic carbons). MS m/z:ꢀ 564.65ꢀ (M+). Anal. Calcd for
fromꢀ2-propanol.
C27H24N4O6S2:ꢀC,ꢀ57.43;ꢀH,ꢀ4.28;ꢀN,ꢀ9.92.ꢀFound:ꢀC,ꢀ57.38;ꢀH,ꢀ
2-((Phenylaminosulfonyl)ꢀmethyl)-5-((1′,3′-diphenyl-5′- 4.61; N, 9.74.

1296
Vol. 61, No. 12
2-((p-Chlorophenylaminosulfonyl)ꢀmethyl)-5-((3′-phenyl-5′- was used as the standard. The percent of scavenging of H2O2
( p-chlorophenyl)ꢀisoxazol-4′-ylsulfonyl)ꢀmethyl)-1,3,4- was calculated by the following equation
oxadiazole (7c):ꢀ Whiteꢀ solid,ꢀ yieldꢀ 76%,ꢀ mpꢀ 170–172°C.ꢀ IRꢀ
% of scavenging=[(Acontrol − Asample ) / Ablank ]×100
(KBr) cm−1:ꢀ1141,ꢀ1332ꢀ(SO2), 1585 (C=N), 1627 (C=C), 3279
1
(NH). H-NMRꢀ (DMSO-d6) δ:ꢀ 5.37ꢀ (s,ꢀ 2H,ꢀ CH2-(C-5)),ꢀ 5.57ꢀ where Acontrol is the absorbance of the control reaction (con-
(s, 2H, CH2-(C-2)),ꢀ7.30–7.89ꢀ(m,ꢀ13H,ꢀAr-H),ꢀ10.68ꢀ(brꢀs,ꢀ1H,ꢀ taining all reagents and ascorbic acid), Asample is the absor-
NH). 13C-NMRꢀ (DMSO-d6) δ:ꢀ 48.6ꢀ (CH2-(C-5)),ꢀ 52.5ꢀ (CH2- bance of the test compound (containing all reagents and test
(C-2)),ꢀ138.8ꢀ(C-4′),ꢀ147.9ꢀ(C-3′),ꢀ153.3ꢀ(C-5′),ꢀ158.4ꢀ(C-),ꢀ159.4ꢀ compound) and Ablank is the absorbance of the blank (contain-
(C-2),ꢀ 126.7,ꢀ 127.6,ꢀ 128.2,ꢀ 129.7,ꢀ 130.5,ꢀ 130.9,ꢀ 132.2,ꢀ 135.1ꢀ ing only reagents). Tests were carried out in triplicate.
(aromatic carbons). MS m/z:ꢀ 605.49ꢀ (M+). Anal. Calcd for
C25H18Cl2N4O6S2:ꢀC,ꢀ49.59;ꢀH,ꢀ2.99;ꢀN,ꢀ9.25.ꢀFound:ꢀC,ꢀ49.81;ꢀ
Acknowledgment The authors are grateful to Council of
H, 3.14; N, 9.39.
Scientificꢀ andꢀ Industrialꢀ Researchꢀ (CSIR),ꢀ Newꢀ Delhi,ꢀ Indiaꢀ
Antioxidant Activity The compounds 3–7 were tested for forꢀfinancialꢀassistanceꢀunderꢀmajorꢀresearchꢀproject.
antioxidant property by DPPH, NO, and H2O2 methods.
DPPH Radical Scavenging Activity The hydrogen atom
or electron donation ability of the compounds was measured
from the bleaching of the purple colored methanol solution of
DPPH. The spectrophotometric assay uses the stable radical
DPPH as a reagent. To 4mL of 0.004% w/v methanol solution
of DPPH, 1mL of various concentrations of the test com-
pounds (50, 75, 100µg/mL) in methanol were added. After
30min incubation period at room temperature, the absorbance
was read against blank at 517nm. Ascorbic acid was used as
the standard. The percent of inhibition (I%) of free radical
production from DPPH was calculated by the following equa-
tion
References
ꢀ 1)ꢀ Balkenhohlꢀ F.,ꢀ vonꢀ demꢀ Bussche-Hünnefeldꢀ C.,ꢀ Lanskyꢀ A.,ꢀ Zechelꢀ
C., Angew. Chem. Int. Ed. Engl., 35, 2288–2337 (1996).
ꢀ 2)ꢀ DolleꢀR.ꢀE.,ꢀJ. Comb. Chem., 6, 623–679 (2004).
3) Cragg G. M., Grothaus P. G., Newman D. J., Chem. Rev., 109,
3012–3043 (2009).
4) Makaritis A., Georgiadis D., Dive V., Yiotakis A., Chemistry, 9,
2079–2094 (2003).
ꢀ 5)ꢀ DallanoceꢀC.,ꢀFrigerioꢀF.,ꢀDeꢀAmiciꢀM.,ꢀDorschꢀS.,ꢀKlotzꢀK.-N.,ꢀDeꢀ
Micheli C., Bioorg. Med. Chem., 15, 2533–2543 (2007).
ꢀ 6)ꢀ Lilienkampfꢀ A.,ꢀ Maoꢀ J.,ꢀ Wanꢀ B.,ꢀ Wangꢀ Y.,ꢀ Franzblauꢀ S.ꢀ G.,ꢀ
Kozikowski A. P., J. Med. Chem., 52, 2109–2118 (2009).
ꢀ 7)ꢀ Lilienkampfꢀ A.,ꢀ Pieroniꢀ M.,ꢀ Wanꢀ B.,ꢀ Wangꢀ Y.,ꢀ Franzblauꢀ S.ꢀ G.,ꢀ
Kozikowski A. P., J. Med. Chem., 53, 678–688 (2010).
ꢀ 8)ꢀ KimataꢀA.,ꢀNakagawaꢀH.,ꢀOhyamaꢀR.,ꢀFukuuchiꢀT.,ꢀOhtaꢀS.,ꢀDoh-
ura K., Suzuki T., Miyata N., J. Med. Chem., 50, 5053–5056 (2007).
9) Castagnolo D., Manetti F., Radi M., Bechi B., Pagano M., De Logu
A., Meleddu R., Saddi M., Botta M., Bioorg. Med. Chem., 17, 5716–
5721 (2009).
10)ꢀ Musserꢀ J.ꢀ H.,ꢀ Brownꢀ R.ꢀ E.,ꢀ Loevꢀ B.,ꢀ Baileyꢀ K.,ꢀ Jonesꢀ H.,ꢀ Kahenꢀ
R.,ꢀ Huangꢀ F.,ꢀ Khandwalaꢀ A.,ꢀ Leibowitzꢀ M.,ꢀ Sonnino-Goldmanꢀ P.,ꢀ
Donigi-RuzzaꢀD.,ꢀJ. Med. Chem., 27, 121–125 (1984).
11) Tan T. M. C., Chen Y., Kong K. H., Bai J., Li Y., Lim S. G., Ang T.
H., Lam Y., Antiviral Res., 71, 7–14 (2006).
12) Akhter M., Husain A., Azad B., Ajmal M., Eur. J. Med. Chem., 44,
2372–2378 (2009).
13)ꢀ Aboraiaꢀ A.ꢀ S.,ꢀ Abdel-Rahmanꢀ H.ꢀ M.,ꢀ Mahfouzꢀ N.ꢀ M.,ꢀ EL-Gendyꢀ
M. A., Bioorg. Med. Chem., 14, 1236–1246 (2006).
14)ꢀ Bakhtꢀ M.ꢀ A.,ꢀ Yarꢀ M.ꢀ S.,ꢀ Abdel-Hamidꢀ S.ꢀ G.,ꢀ Alꢀ Qasoumiꢀ S.ꢀ I.,ꢀ
Samad A., Eur. J. Med. Chem., 45, 5862–5869 (2010).
15)ꢀ Liuꢀ F.,ꢀ Luoꢀ X.ꢀ Q.,ꢀ Songꢀ B.ꢀ A.,ꢀ Bhaduryꢀ P.ꢀ S.,ꢀ Yangꢀ S.,ꢀ Jinꢀ L.ꢀ H.,ꢀ
XueꢀW.,ꢀHuꢀD.ꢀY.,ꢀBioorg. Med. Chem., 16, 3632–3640 (2008).
16) Jha K. K., Samad A., Kumar Y., Shaharyar M., Khosa R. L., Jain J.,
Kumar V., Singh P., Eur. J. Med. Chem., 45, 4963–4967 (2010).
17) Khanum S. A., Shashikanth S., Umesha S., Kavitha R., Eur. J. Med.
Chem., 40, 1156–1162 (2005).
I%=[(Acontrol − Asample ) / Ablank ]×100
where Acontrol is the absorbance of the control reaction (con-
taining methanolic DPPH and ascorbic acid), Asample is the ab-
sorbance of the test compound (containing methanolic DPPH
and test compound) and Ablank is the absorbance of the blank
(containing only methanolic DPPH). Tests were carried out in
triplicate.
NO Scavenging Activity NO scavenging activity was
measuredꢀbyꢀslightlyꢀmodifiedꢀmethodsꢀofꢀGreenꢀet al.33) and
Marcocci et al.34) NO radicals were generated from sodium
nitroprusside. One milliliter of sodium nitroprusside (10mM)
and 1.5mL of phosphate buffer saline (0.2M, pH 7.4) were
added to different concentrations (50, 75, 100µg/mL) of the
test compounds and incubated at 25°C for 150min. After in-
cubation, 1mL of the reaction mixture was treated with 1mL
of Griess reagent (1% sulfanilamide, 2% H3PO4 and 0.1%
naphthylethylenediamine dihydrochloride). The absorbance of
the chromatophore was measured at 546nm. Ascorbic acid
was used as the standard. Nitric oxide scavenging activity was
calculated by the following equation
18) Naveena C. S., Boja P., Kumari N. S., Eur. J. Med. Chem., 45,
4708–4719 (2010).
% of scavenging=[(Acontrol − Asample ) / Ablank ]×100
19) Chen C. J., Song B. A., Yang S., Xu G. F., Bhadury P. S., Jin L. H.,
Huꢀ D.ꢀ Y.,ꢀ Liꢀ Q.ꢀ Z.,ꢀ Liuꢀ F.,ꢀ Xueꢀ W.,ꢀ Luꢀ P.,ꢀ Chenꢀ Z.,ꢀ Bioorg. Med.
Chem., 15, 3981–3989 (2007).
20) Baraldi P. G., Bovero A., Fruttarolo F., Romagnoli R., Tabrizi M.
A., Preti D., Varani K., Borea P. A., Moorman A. R., Bioorg. Med.
Chem., 11, 4161–4169 (2003).
where Acontrol is the absorbance of the control reaction (con-
taining all reagents and ascorbic acid), Asample is the absor-
bance of the test compound (containing all reagents and test
compound) and Ablank is the absorbance of the blank (contain-
ing only reagents). Tests were carried out in triplicate.
H2O2 Scavenging Activity The H2O2 scavenging ability
of the test compound was determined according to the method
of Ruch et al.35) A solution of H2O2 (40 mM) was prepared in
phosphate buffer (pH 7.4). Fifty, 75 and 100µg/mL concentra-
tions of the test compounds in 3.4mL phosphate buffer were
added to H2O2 solution (0.6mL, 40mM). The absorbance value
of the reaction mixture was recorded at 230nm. Ascorbic acid
21)ꢀ CardiaꢀM.ꢀC.,ꢀCordaꢀL.,ꢀFaddaꢀA.ꢀM.,ꢀMaccioniꢀA.ꢀM.,ꢀMaccioniꢀE.,ꢀ
Plumitallo A., IL Farmaco, 53, 698–708 (1998).
22)ꢀ FaragꢀA.ꢀM.,ꢀMayhoubꢀA.ꢀS.,ꢀBarakatꢀS.ꢀE.,ꢀBayomiꢀA.ꢀH.,ꢀBioorg.
Med. Chem., 16, 881–889 (2008).
23)ꢀ XiaꢀY.,ꢀFanꢀC.ꢀD.,ꢀZhaoꢀB.ꢀX.,ꢀZhaoꢀJ.,ꢀShinꢀD.ꢀS.,ꢀMiaoꢀJ.ꢀY.,ꢀEur.
J. Med. Chem., 43, 2347–2353 (2008).
24) Bozzo F., Bassignana A., Lazzarato L., Boschi D., Gasco A., Bocca

December 2013
C., Miglietta A., Chem. Biol. Interact., 182, 183–190 (2009).
1297
31) Burits M., Bucar F., Phytother. Res., 14, 323–328 (2000).
25) Bhat B. A., Dhar K. L., Puri S. C., Saxena A. K., Shanmugavel M.,
QaziꢀG.ꢀN.,ꢀBioorg. Med. Chem. Lett., 15, 3177–3180 (2005).
26) Mallikarjuna Reddy G., Ramachandra Reddy P., Padmavathi V.,
Padmaja A., Arch. Pharm. Chem. Life Sci., 346, 154–162 (2013).
27) Padmaja A., Muralikrishna A., Rajasekhar C., Padmavathi V.,
Chem. Pharm. Bull., 59, 1509–1517 (2011).
32)ꢀ Cuendetꢀ M.,ꢀ Hostettmannꢀ K.,ꢀ Potteratꢀ O.,ꢀ Dyatmikoꢀ W.,ꢀ Helv.
Chim. Acta, 80, 1144–1152 (1997).
33)ꢀ GreenꢀL.ꢀC.,ꢀWagnerꢀD.ꢀA.,ꢀGlogowskiꢀJ.,ꢀSkipperꢀP.ꢀL.,ꢀWishnokꢀJ.ꢀ
S., Tannenbaum S. R., Anal. Biochem., 126, 131–138 (1982).
34) Marcocci L., Maguire J. J., Droy–Lefaix M. T., Packer L., Biochem.
Biophys. Res. Commun., 201, 748–755 (1994).
28) Padmavathi V., Nagi Reddy S., Mahesh K., Chem. Pharm. Bull., 57,
1376–1380 (2009).
35)ꢀ Ruchꢀ R.ꢀ J.,ꢀ Chengꢀ S.ꢀ J.,ꢀ Klaunigꢀ J.ꢀ E.,ꢀ Carcinogenesis, 10, 1003–
1008 (1989).
29)ꢀ Simovicꢀ D.,ꢀ Diꢀ M.,ꢀ Marksꢀ V.,ꢀ Chatfieldꢀ D.ꢀ C.,ꢀ Reinꢀ K.ꢀ S.,ꢀ J. Org. 36) Venkata Ramana Reddy M., Reddy S., Synthesis, 4, 322–323 (1984).
Chem., 72, 650–653 (2007).
30) Padmavathi V., Venugopal K., Balaiah A., Venkata Ramana Reddy
T., Bhaskar Reddy D., Heteroatom Chem., 13, 677–682 (2002).
37) Venkata Ramana Reddy M., Reddy S., Bashkar Reddy D., Padma-
vathi V., Synth. Commun., 19, 1101–1107 (1989).